Abstract Candida albicans is an opportunistic pathogen that is normally maintained in a benign state in non- sterile body sites by the action of the innate immune system, including phagocytic cells such as macrophages and neutrophils. When these barriers are compromised, Candida can extend beyond sites of commensal colonization to cause deep-seated infections. It is now the third most common cause of bloodstream infections in hospitalized patients and is associated with a 40-50% mortality rate. A model system in which Candida and macrophages are co-cultured has become a valuable and robust model of host-pathogen interactions capable of identifying novel virulence attributes of this organism and host strategies for antifungal containment. The interaction is dynamic, with the fungal cell switching to a filamentous, hyphal, morphology within the macrophage phagolysosome, neutralizing this ostensibly acidic organelle and, eventually, inducing pyroptosis, a pro-inflammatory cell death pathway, culminating in the rupture of the macrophage. Two competing, but not entirely irreconcilable, models exist for how C. albicans disrupts normal phagolysosome integrity. In the first, proposed by our laboratory and supported by genetic and genomic data, the phagocytosed C. albicans cell begins catabolizing less preferred carbon sources, including amino acids, carboxylic acids, and N- acetylglucosamine. A byproduct of this metabolism is the generation of alkaline byproducts that neutralize the extracellular space, including the lumen of the phagolysosome, thus inducing hyphal growth. The second model, very recently proposed by Grinstein and colleagues and supported by biochemical data, suggests that C. albicans cannot out-compete the macrophage machinery that neutralizes the phagolysosome. Rather, another signal (perhaps CO2) induces hyphal growth and this physically disrupts and neutralizes the phagolysosome. This proposal includes rigorous and sophisticated cell biological and genetic experiments to resolve these questions and develop a unified model to explain the Candida-macrophage interaction. We include tools to assess phagolysosomal pH and integrity via fluorescence microscopy using engineered control of morphology and metabolism to delinate the temporal course of events that result in fungal escape. Further, we will test two alternative hypotheses for hyphal induction. The second of these brings together the most compelling aspects of both models to propose and test a novel mechanism of hyphal induction based on alkalinization of the C. albicans cytosol. Given the wide adoption of this model system, it is critical that we understand the fundamental elements of the Candida-macrophage interaction to clarify future goals in this field.